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Cancers, Volume 15, Issue 21 (November-1 2023) – 193 articles

Cover Story (view full-size image): Many cancer survivors report symptoms long after completing their cancer treatment. This can impact their quality of life and ability to return to daily activities, including the ability to work. We explored symptoms and their severity reported by 561 cancer survivors after primary cancer treatment with curative intent who were attending the Sydney Cancer Survivorship Centre clinic in Sydney, Australia, for the first time. We were interested in how symptoms clustered together and the impact of symptoms and symptom clusters on the ability to work. We found that survivors who reported higher rates of pain, emotional and cognitive clusters of symptoms were more likely to be limited in their ability to work. View this paper
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18 pages, 1603 KiB  
Review
Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma
by Ilias D. Vachliotis, Ioannis Valsamidis and Stergios A. Polyzos
Cancers 2023, 15(21), 5306; https://doi.org/10.3390/cancers15215306 - 06 Nov 2023
Cited by 3 | Viewed by 1282
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-α and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations. Full article
(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)
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20 pages, 26644 KiB  
Article
Exosomal Long Non-Coding Ribonucleic Acid Ribonuclease Component of Mitochondrial Ribonucleic Acid Processing Endoribonuclease Is Defined as a Potential Non-Invasive Diagnostic Biomarker for Bladder Cancer and Facilitates Tumorigenesis via the miR-206/G6PD Axis
by Yuting Gao, Xuan Wang, Huarong Luo, Chen Chen, Jing Li, Ruixin Sun, Dong Li and Zujun Sun
Cancers 2023, 15(21), 5305; https://doi.org/10.3390/cancers15215305 - 06 Nov 2023
Viewed by 934
Abstract
Bladder cancer (BLCA) is one of the cancers that is highly sensitive to specific non-invasive tumor biomarkers that facilitate early diagnosis. Exosome-derived long non-coding RNAs (lncRNAs) hold promise as diagnostic biomarkers for BLCA. In this study, we employed RNA-sequencing to compare the expression [...] Read more.
Bladder cancer (BLCA) is one of the cancers that is highly sensitive to specific non-invasive tumor biomarkers that facilitate early diagnosis. Exosome-derived long non-coding RNAs (lncRNAs) hold promise as diagnostic biomarkers for BLCA. In this study, we employed RNA-sequencing to compare the expression patterns of lncRNAs in urine exosomes from three BLCA patients and three healthy individuals. RMRP displayed the most significant differential expression. Elevated RMRP expression levels were observed in urinary and plasma exosomes from BLCA patients compared with those from healthy individuals. RMRP exhibited significant associations with certain BLCA patient clinicopathological features, including tumor stage, poor prognosis, and tumor grade. Combined diagnosis using RMRP in urine and plasma exosomes demonstrated a superior diagnostic performance with receiver operating characteristic curve analysis. RMRP was found to be related to BLCA tumor progression and the cell migration and invasion processes via the miR-206/G6PD axis both in vitro and in vivo. Mechanistically, RMRP serves as an miR-206 sponge, as suggested by dual-luciferase reporter assays and RNA immunoprecipitation. Our study suggests that the combined diagnosis of RMRP in urinary and plasma exosomes can serve as an excellent non-invasive diagnostic biomarker for BLCA patients. Additionally, targeting the RMRP/miR-206/G6PD axis holds promise as a therapeutic strategy for BLCA. Full article
(This article belongs to the Section Cancer Biomarkers)
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12 pages, 1331 KiB  
Article
Long-Term Usage of Proton Pump Inhibitors Associated with Prognosis in Patients with Colorectal Cancer
by Chin-Chia Wu, Chuan-Yin Fang, Ben-Hui Yu, Chun-Ming Chang, Ta-Wen Hsu, Chung-Lin Hung, Shih-Kai Hung, Wen-Yen Chiou and Jui-Hsiu Tsai
Cancers 2023, 15(21), 5304; https://doi.org/10.3390/cancers15215304 - 06 Nov 2023
Cited by 1 | Viewed by 1038
Abstract
The dose–response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with [...] Read more.
The dose–response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with different cumulative proton pump inhibitor dose levels. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2005 to 2020. After frequency matching with a 1:1 ratio, a total of 20,889 users with proton pump inhibitors and 20,889 without proton pump inhibitors were analyzed. The cumulative defined daily dose level of proton pump inhibitor was stratified to explore the dose–response relationship. A proton pump inhibitor exposure cumulative defined daily dose > 60 after colorectal cancer diagnosis had higher risk of all-cause death than non-proton pump inhibitor users with adjusted hazard ratios of 1.10 (95% CIs: 1.04–1.18). For recurrence, a proton pump inhibitor exposure cumulative defined daily dose > 60 had reduced recurrence risk with an adjusted hazard ratio of 0.84 (95% CIs: 0.76–0.93). This study demonstrated that the long-term use of proton pump inhibitors in patients with colorectal cancer was associated with an increased risk of death that related to the proton pump inhibitor exposure cumulative defined daily dose > 60 and had different dose–response effect in various dose level. Full article
(This article belongs to the Special Issue Colorectal Cancer: Epidemiology and Prevention)
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15 pages, 6752 KiB  
Article
An Interpretable Radiomics Model Based on Two-Dimensional Shear Wave Elastography for Predicting Symptomatic Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma
by Xian Zhong, Zohaib Salahuddin, Yi Chen, Henry C. Woodruff, Haiyi Long, Jianyun Peng, Xiaoyan Xie, Manxia Lin and Philippe Lambin
Cancers 2023, 15(21), 5303; https://doi.org/10.3390/cancers15215303 - 06 Nov 2023
Viewed by 946
Abstract
Objective: The aim of this study was to develop and validate an interpretable radiomics model based on two-dimensional shear wave elastography (2D-SWE) for symptomatic post-hepatectomy liver failure (PHLF) prediction in patients undergoing liver resection for hepatocellular carcinoma (HCC). Methods: A total of 345 [...] Read more.
Objective: The aim of this study was to develop and validate an interpretable radiomics model based on two-dimensional shear wave elastography (2D-SWE) for symptomatic post-hepatectomy liver failure (PHLF) prediction in patients undergoing liver resection for hepatocellular carcinoma (HCC). Methods: A total of 345 consecutive patients were enrolled. A five-fold cross-validation was performed during training, and the models were evaluated in the independent test cohort. A multi-patch radiomics model was established based on the 2D-SWE images for predicting symptomatic PHLF. Clinical features were incorporated into the models to train the clinical–radiomics model. The radiomics model and the clinical–radiomics model were compared with the clinical model comprising clinical variables and other clinical predictive indices, including the model for end-stage liver disease (MELD) score and albumin–bilirubin (ALBI) score. Shapley Additive exPlanations (SHAP) was used for post hoc interpretability of the radiomics model. Results: The clinical–radiomics model achieved an AUC of 0.867 (95% CI 0.787–0.947) in the five-fold cross-validation, and this score was higher than that of the clinical model (AUC: 0.809; 95% CI: 0.715–0.902) and the radiomics model (AUC: 0.746; 95% CI: 0.681–0.811). The clinical–radiomics model showed an AUC of 0.822 in the test cohort, higher than that of the clinical model (AUC: 0.684, p = 0.007), radiomics model (AUC: 0.784, p = 0.415), MELD score (AUC: 0.529, p < 0.001), and ALBI score (AUC: 0.644, p = 0.016). The SHAP analysis showed that the first-order radiomics features, including first-order maximum 64 × 64, first-order 90th percentile 64 × 64, and first-order 10th percentile 32 × 32, were the most important features for PHLF prediction. Conclusion: An interpretable clinical–radiomics model based on 2D-SWE and clinical variables can help in predicting symptomatic PHLF in HCC. Full article
(This article belongs to the Collection Artificial Intelligence in Oncology)
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9 pages, 632 KiB  
Article
Axillary Reverse Mapping in Clinically Node-Positive Breast Cancer Patients
by Masakuni Noguchi, Masafumi Inokuchi, Miki Yokoi-Noguchi, Emi Morioka, Yusuke Haba, Tomoko Takahashi, Akihiro Shioya and Sohsuke Yamada
Cancers 2023, 15(21), 5302; https://doi.org/10.3390/cancers15215302 - 06 Nov 2023
Viewed by 836
Abstract
Background: Axillary reverse mapping (ARM) nodes are involved in a significant proportion of clinically node-positive (cN+) breast cancer patients. However, neoadjuvant chemotherapy (NAC) is effective at decreasing the incidence of nodal metastases in cN+ patients. Patients and methods: One hundred forty-five cN+ patients [...] Read more.
Background: Axillary reverse mapping (ARM) nodes are involved in a significant proportion of clinically node-positive (cN+) breast cancer patients. However, neoadjuvant chemotherapy (NAC) is effective at decreasing the incidence of nodal metastases in cN+ patients. Patients and methods: One hundred forty-five cN+ patients with confirmed nodal involvement on ultrasound-guided fine needle aspiration cytology were enrolled in this study: one group underwent axillary lymph node dissection (ALND) without NAC (upfront surgery group), and the other group underwent ALND following NAC (NAC group). The patients underwent 18F-FDG-positron emission tomography/computed tomography (18F-FDG-PET/CT) before surgery, as well as an ARM procedure during ALND. Results: the rates of involvement of ARM nodes in the NAC group were significantly lower than those of the upfront surgery group (36.6% vs. 62.2%, p < 0.01). Notably, involvement was significantly decreased after NAC in non-luminal-type tumors as compared to the luminal-type (18.4% vs. 48.5%: p < 0.01). Moreover, there was a significant difference in ARM node involvement after NAC between patients with or without axillary uptake of 18F-FDG (61.5% vs. 32.5%: p < 0.01). Conclusions: NAC significantly decreased the risk of ARM node metastases in cN+ patients, but 18F-FDG-PET/CT was not suitable to detect residual metastatic disease of the axilla after NAC. Full article
(This article belongs to the Special Issue Conservative Axillary Surgery for Breast Cancer)
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19 pages, 1187 KiB  
Review
Role of Tumor Microenvironment in Pituitary Neuroendocrine Tumors: New Approaches in Classification, Diagnosis and Therapy
by Dana Antonia Tapoi, Maria-Linda Popa, Cristiana Tanase, Diana Derewicz and Ancuța-Augustina Gheorghișan-Gălățeanu
Cancers 2023, 15(21), 5301; https://doi.org/10.3390/cancers15215301 - 06 Nov 2023
Viewed by 1289
Abstract
Adenohypophysal pituitary tumors account for 10–15% of all intracranial tumors, and 25–55% display signs of invasiveness. Nevertheless, oncology still relies on histopathological examination to establish the diagnosis. Considering that the classification of pituitary tumors has changed significantly in recent years, we discuss the [...] Read more.
Adenohypophysal pituitary tumors account for 10–15% of all intracranial tumors, and 25–55% display signs of invasiveness. Nevertheless, oncology still relies on histopathological examination to establish the diagnosis. Considering that the classification of pituitary tumors has changed significantly in recent years, we discuss the definition of aggressive and invasive tumors and the latest molecular criteria used for classifying these entities. The pituitary tumor microenvironment (TME) is essential for neoplastic development and progression. This review aims to reveal the impact of TME characteristics on stratifying these tumors in view of finding appropriate therapeutic approaches. The role of the pituitary tumor microenvironment and its main components, non-tumoral cells and soluble factors, has been addressed. The variable display of different immune cell types, tumor-associated fibroblasts, and folliculostellate cells is discussed in relation to tumor development and aggressiveness. The molecules secreted by both tumoral and non-tumoral cells, such as VEGF, FGF, EGF, IL6, TNFα, and immune checkpoint molecules, contribute to the crosstalk between the tumor and its microenvironment. They could be considered potential biomarkers for diagnosis and the invasiveness of these tumors, together with emerging non-coding RNA molecules. Therefore, assessing this complex network associated with pituitary neuroendocrine tumors could bring a new era in diagnosing and treating this pathology. Full article
(This article belongs to the Section Cancer Metastasis)
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41 pages, 3221 KiB  
Review
Aptamers as Potential Therapeutic Tools for Ovarian Cancer: Advancements and Challenges
by Wojciech Szymanowski, Anna Szymanowska, Anna Bielawska, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo and Paola Amero
Cancers 2023, 15(21), 5300; https://doi.org/10.3390/cancers15215300 - 06 Nov 2023
Cited by 1 | Viewed by 1467
Abstract
Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of [...] Read more.
Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of effective diagnostic methods, and relapses. Aptamers, synthetic, short single-stranded oligonucleotides, have emerged as promising anticancer therapeutics. Their ability to selectively bind to target molecules, including cancer-related proteins and receptors, has revolutionized drug discovery and biomarker identification. Aptamers offer unique insights into the molecular pathways involved in cancer development and progression. Moreover, they show immense potential as drug delivery systems, enabling targeted delivery of therapeutic agents to cancer cells while minimizing off-target effects and reducing systemic toxicity. In the context of OC, the integration of aptamers with non-coding RNAs (ncRNAs) presents an opportunity for precise and efficient gene targeting. Additionally, the conjugation of aptamers with nanoparticles allows for accurate and targeted delivery of ncRNAs to specific cells, tissues, or organs. In this review, we will summarize the potential use and challenges associated with the use of aptamers alone or aptamer–ncRNA conjugates, nanoparticles, and multivalent aptamer-based therapeutics for the treatment of OC. Full article
(This article belongs to the Special Issue Aptamers and Cancer)
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26 pages, 1105 KiB  
Review
Potential Associations between Vascular Biology and Hodgkin’s Lymphoma: An Overview
by Wellington Francisco Rodrigues, Camila Botelho Miguel, Melissa Carvalho Martins de Abreu, Jamil Miguel Neto and Carlo José Freire Oliveira
Cancers 2023, 15(21), 5299; https://doi.org/10.3390/cancers15215299 - 06 Nov 2023
Viewed by 1473
Abstract
Hodgkin’s lymphoma (HL) is a lymphatic neoplasm typically found in the cervical lymph nodes. The disease is multifactorial, and in recent years, the relationships between various vascular molecules have been explored in the field of vascular biology. The connection between vascular biology and [...] Read more.
Hodgkin’s lymphoma (HL) is a lymphatic neoplasm typically found in the cervical lymph nodes. The disease is multifactorial, and in recent years, the relationships between various vascular molecules have been explored in the field of vascular biology. The connection between vascular biology and HL is intricate and the roles of several pathways remain unclear. This review summarizes the cellular and molecular relationships between vascular biology and HL. Proteins associated with various functions in vascular biology, including cytokines (TNF-α, IL-1, IL-13, and IL-21), chemokines (CXCL10, CXCL12, and CCL21), adhesion molecules (ELAM-1/VCAM-1), and growth factors (BDNF/NT-3, platelet-derived growth factor receptor-α), have been linked to tumor activity. Notable tumor activities include the induction of paracrine activation of NF-kB-dependent pathways, upregulation of adhesion molecule regulation, genome amplification, and effective loss of antigen presentation mediated by MHC-II. Preclinical study models, primarily those using cell culture, have been optimized for HL. Animal models, particularly mice, are also used as alternatives to complex biological systems, with studies primarily focusing on the physiopathogenic evaluation of the disease. These biomolecules warrant further study because they may shed light on obscure pathways and serve as targets for prevention and/or treatment interventions. Full article
(This article belongs to the Section Molecular Cancer Biology)
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13 pages, 1184 KiB  
Article
Survival Improvements in Advanced Hepatocellular Carcinoma with Sequential Therapy by Era
by Yoshiko Nakamura, Masashi Hirooka, Atsushi Hiraoka, Yohei Koizumi, Ryo Yano, Makoto Morita, Yuki Okazaki, Yusuke Imai, Hideko Ohama, Kana Hirooka, Takao Watanabe, Fujimasa Tada, Osamu Yoshida, Yoshio Tokumoto, Masanori Abe and Yoichi Hiasa
Cancers 2023, 15(21), 5298; https://doi.org/10.3390/cancers15215298 - 06 Nov 2023
Viewed by 877
Abstract
Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were [...] Read more.
Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival. Full article
(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)
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18 pages, 1691 KiB  
Review
PI3K/Akt/mTOR Signaling Pathway in Blood Malignancies—New Therapeutic Possibilities
by Wojciech Wiese, Julia Barczuk, Olga Racinska, Natalia Siwecka, Wioletta Rozpedek-Kaminska, Artur Slupianek, Radoslaw Sierpinski and Ireneusz Majsterek
Cancers 2023, 15(21), 5297; https://doi.org/10.3390/cancers15215297 - 05 Nov 2023
Viewed by 1954
Abstract
Blood malignancies remain a therapeutic challenge despite the development of numerous treatment strategies. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a central role in regulating many cellular functions, including cell cycle, proliferation, quiescence, and longevity. Therefore, dysregulation [...] Read more.
Blood malignancies remain a therapeutic challenge despite the development of numerous treatment strategies. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a central role in regulating many cellular functions, including cell cycle, proliferation, quiescence, and longevity. Therefore, dysregulation of this pathway is a characteristic feature of carcinogenesis. Increased activation of PI3K/Akt/mTOR signaling enhances proliferation, growth, and resistance to chemo- and immunotherapy in cancer cells. Overactivation of the pathway has been found in various types of cancer, including acute and chronic leukemia. Inhibitors of the PI3K/Akt/mTOR pathway have been used in leukemia treatment since 2014, and some of them have improved treatment outcomes in clinical trials. Recently, new inhibitors of PI3K/Akt/mTOR signaling have been developed and tested both in preclinical and clinical models. In this review, we outline the role of the PI3K/Akt/mTOR signaling pathway in blood malignancies’ cells and gather information on the inhibitors of this pathway that might provide a novel therapeutic opportunity against leukemia. Full article
(This article belongs to the Section Cancer Therapy)
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16 pages, 1864 KiB  
Article
Risk Biomarkers for Biochemical Recurrence after Radical Prostatectomy for Prostate Cancer Using Clinical and MRI-Derived Semantic Features
by Adalgisa Guerra, Filipe Caseiro Alves, Kris Maes, Rui Maio, Geert Villeirs and Helena Mouriño
Cancers 2023, 15(21), 5296; https://doi.org/10.3390/cancers15215296 - 05 Nov 2023
Viewed by 1024
Abstract
Objectives: This study aimed to assess the impact of the covariates derived from a predictive model for detecting extracapsular extension on pathology (pECE+) on biochemical recurrence-free survival (BCRFS) within 4 years after robotic-assisted radical prostatectomy (RARP). Methods: Retrospective data analysis was conducted from [...] Read more.
Objectives: This study aimed to assess the impact of the covariates derived from a predictive model for detecting extracapsular extension on pathology (pECE+) on biochemical recurrence-free survival (BCRFS) within 4 years after robotic-assisted radical prostatectomy (RARP). Methods: Retrospective data analysis was conducted from a single center between 2015 and 2022. Variables under consideration included prostate-specific antigen (PSA) levels, patient age, prostate volume, MRI semantic features, and Grade Group (GG). We also assessed the influence of pECE+ and positive surgical margins on BCRFS. To attain these goals, we used the Kaplan–Meier survival function and the multivariable Cox regression model. Additionally, we analyzed the MRI features on BCR (biochemical recurrence) in low/intermediate risk patients. Results: A total of 177 participants with a follow-up exceeding 6 months post-RARP were included. The 1-year, 2-year, and 4-year risks of BCR after radical prostatectomy were 5%, 13%, and 21%, respectively. The non-parametric approach for the survival analysis showed that adverse MRI features such as macroscopic ECE on MRI (mECE+), capsular disruption, high tumor capsular contact length (TCCL), GG ≥ 4, positive surgical margins (PSM), and pECE+ on pathology were risk factors for BCR. In low/intermediate-risk patients (pECE− and GG < 4), the presence of adverse MRI features has been shown to increase the risk of BCR. Conclusions: The study highlights the importance of incorporating predictive MRI features for detecting extracapsular extension pre-surgery in influencing early outcomes and clinical decision making; mECE+, TCCL, capsular disruption, and GG ≥ 4 based on pre-surgical biopsy were independent prognostic factors for early BCR. The presence of adverse features on MRI can assist in identifying low/intermediate-risk patients who will benefit from closer monitoring. Full article
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28 pages, 20889 KiB  
Review
Radical Hysterectomy or Total Mesometrial Resection—Two Anatomical Concepts for Surgical Treatment of Cancer of the Uterine Cervix
by Stoyan Kostov, Pavel Sorokin, Bruno Rezende, Hakan Yalçın and Ilker Selçuk
Cancers 2023, 15(21), 5295; https://doi.org/10.3390/cancers15215295 - 05 Nov 2023
Viewed by 1837
Abstract
A radical hysterectomy is the standard method of surgical treatment for patients with early-stage cancer of the uterine cervix. It was first introduced more than 100 years ago. Since then, various and many different radical procedures, which diverge in terms of radicality, have [...] Read more.
A radical hysterectomy is the standard method of surgical treatment for patients with early-stage cancer of the uterine cervix. It was first introduced more than 100 years ago. Since then, various and many different radical procedures, which diverge in terms of radicality, have been described. Inconsistencies are clearly seen in practical anatomy, which were defined as surgically created artifacts. Moreover, the disparity of the procedure is most notable regarding the terminology of pelvic connective tissues and spaces. Despite these controversies, the procedure is widely performed and implemented in the majority of guidelines for the surgical treatment of cancer of the uterine cervix. However, a different and unique concept of surgical treatment of cervical cancer has been reported. It is based on ontogenetic anatomy and maps any tissue in the mature organism according to its embryologic development. The clinical implementation of this theory in the context of early cervical cancer is total mesometrial resection. The present article aims to describe and compare the anatomical and surgical basics of a radical hysterectomy (type C1/C2) and total mesometrial resection. Discrepancies regarding the terminology, resection lines, and surgical planes of both procedures are highlighted in detail. The surgical anatomy of the pelvic autonomic nerves and its surgical dissection is also delineated. This is the first article that compares the discrepancy of classic anatomy and ontogenic anatomy regarding surgical treatment of cancer of the uterine cervix. Clinical data, oncological outcome, and neoadjuvant and adjuvant treatment regarding both procedures are not the topic of the present article. Full article
(This article belongs to the Section Cancer Therapy)
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20 pages, 1432 KiB  
Review
The Role of Macrophages in Sarcoma Tumor Microenvironment and Treatment
by Agnieszka E. Zając, Anna M. Czarnecka and Piotr Rutkowski
Cancers 2023, 15(21), 5294; https://doi.org/10.3390/cancers15215294 - 05 Nov 2023
Cited by 2 | Viewed by 6798
Abstract
Sarcomas are a heterogeneous group of malignant mesenchymal tumors, including soft tissue and bone sarcomas. Macrophages in the tumor microenvironment, involved in immunosuppression and leading to tumor development, are called tumor-associated macrophages (TAMs). TAMs are very important in modulating the microenvironment of sarcomas [...] Read more.
Sarcomas are a heterogeneous group of malignant mesenchymal tumors, including soft tissue and bone sarcomas. Macrophages in the tumor microenvironment, involved in immunosuppression and leading to tumor development, are called tumor-associated macrophages (TAMs). TAMs are very important in modulating the microenvironment of sarcomas by expressing specific markers and secreting factors that influence immune and tumor cells. They are involved in many signaling pathways, such as p-STAT3/p-Erk1/2, PI3K/Akt, JAK/MAPK, and JAK/STAT3. TAMs also significantly impact the clinical outcomes of patients suffering from sarcomas and are mainly related to poor overall survival rates among bone and soft tissue sarcomas, for example, chondrosarcoma, osteosarcoma, liposarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma. This review summarizes the current knowledge on TAMs in sarcomas, focusing on specific markers on sarcoma cells, cell–cell interactions, and the possibly involved molecular pathways. Furthermore, we discuss the clinical significance of macrophages in sarcomas as a potential target for new therapies, presenting clinical relevance, possible new treatment options, and ongoing clinical trials using TAMs in sarcoma treatment. Full article
(This article belongs to the Special Issue Feature Review for Cancer Therapy)
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14 pages, 1652 KiB  
Review
Cancer-Associated Abdominal Vein Thrombosis
by Lorna Muscat-Baron, Amber Leigh Borg, Laura Maria Attard, Alex Gatt and Nicoletta Riva
Cancers 2023, 15(21), 5293; https://doi.org/10.3390/cancers15215293 - 04 Nov 2023
Viewed by 1431
Abstract
Cancer is associated with an increased risk of developing venous thromboembolism, due to its direct influence on the three pillars of Virchow’s triad (e.g., compression on the blood vessels by the tumour, blood vessels invasion, and cytokine release), together with the effect of [...] Read more.
Cancer is associated with an increased risk of developing venous thromboembolism, due to its direct influence on the three pillars of Virchow’s triad (e.g., compression on the blood vessels by the tumour, blood vessels invasion, and cytokine release), together with the effect of exogenous factors (such as chemotherapy, radiotherapy, surgery). In cancer patients, the risk of thrombosis at unusual sites, such as splanchnic, ovarian and renal vein thrombosis, is also increased. Abdominal vein thromboses are frequently incidental findings on abdominal imaging performed as part of the diagnostic/staging workup or the follow-up care of malignancies. There is little evidence on the management of unusual site venous thromboembolism in cancer patients since there are only a few specific recommendations; thus, the management follows the general principles of the treatment of cancer-associated deep vein thrombosis and pulmonary embolism. This narrative review summarises the latest evidence on cancer-associated abdominal vein thrombosis, i.e., thrombosis of the splanchnic, ovarian and renal veins. Full article
(This article belongs to the Special Issue Venous Thromboembolism and Cancer)
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12 pages, 6019 KiB  
Article
Transoral Ultrasound in the Outpatient Clinic for the Diagnostic Work-Up of Oropharyngeal Cancer: A Feasibility Study
by Martin Garset-Zamani, Rikke Norling, Christoffer Holst Hahn, Tina Klitmøller Agander, Christian von Buchwald and Tobias Todsen
Cancers 2023, 15(21), 5292; https://doi.org/10.3390/cancers15215292 - 04 Nov 2023
Cited by 2 | Viewed by 1085
Abstract
Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a [...] Read more.
Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a single-center prospective diagnostic accuracy study including patients with suspected or biopsy-verified OPCs during outpatient appointments. All patients were offered transoral US and MRI. If transoral US could not be tolerated by the patient, transcervical US was performed. The primary outcome was the diagnostic accuracy of detecting OPCs with US compared to MRI, using histopathology as the reference standard. The secondary outcome was comparing the primary tumor diameters between US and MRI blinded to each other. Out of the 26 patients included in the study, 21 (81%) had OPCs. Transoral US could be performed in 21/21 and 1/5 patients with suspected palatine and lingual tonsil OPCs, respectively. Overall, US diagnostic accuracy was 92%, compared to 81% with MRI (p = 0.37). US and MRI had a high correlation between tumor diameters in the anteroposterior diameter (R = 0.80, p < 0.001), corresponding to the depth axis on US. In conclusion, this small study showed the promise and feasibility of transoral US to improve the initial clinical evaluations of patients with suspected OPCs. Full article
(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Oropharyngeal Cancers)
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14 pages, 329 KiB  
Review
Clinical Advances and Future Directions of Oncolytic Virotherapy for Head and Neck Cancer
by Zhan Wang, Peng Sun, Zhiyong Li and Shaowen Xiao
Cancers 2023, 15(21), 5291; https://doi.org/10.3390/cancers15215291 - 04 Nov 2023
Cited by 2 | Viewed by 3546
Abstract
Oncolytic viruses (OVs), without harming normal tissues, selectively infect and replicate within tumor cells, to release immune molecules and tumor antigens, achieving immune-mediated destruction of tumors and making them one of the most promising immunotherapies for cancer. Many clinical studies have demonstrated that [...] Read more.
Oncolytic viruses (OVs), without harming normal tissues, selectively infect and replicate within tumor cells, to release immune molecules and tumor antigens, achieving immune-mediated destruction of tumors and making them one of the most promising immunotherapies for cancer. Many clinical studies have demonstrated that OVs can provide clinical benefits for patients with different types of tumors, at various stages, including metastatic and previously untreatable cases. When OVs are used in combination with chemotherapy, radiotherapy, immunotherapy, and other treatments, they can synergistically enhance the therapeutic effects. The concept of oncolytic virotherapy (OVT) was proposed in the early 20th century. With advancements in genetic engineering, genetically modified viruses can further enhance the efficacy of cancer immunotherapy. In recent years, global research on OV treatment of malignant tumors has increased dramatically. This article comprehensively reviews the findings from relevant research and clinical trials, providing an overview of the development of OVT and its application in the clinical treatment of head and neck cancer. The aim is to offer insights for future clinical and fundamental research on OVT. Full article
(This article belongs to the Special Issue Advances in Head and Neck Cancer Research)
16 pages, 1031 KiB  
Article
Excellent Outcomes in Children, Adolescents, and Young Adults with Ovarian Germ Cell Tumors Treated by Either Reduced- or Standard-Dose Bleomycin
by Meerim Park, Jin Kyung Suh, Jun Ah Lee, Hyeon Jin Park, Eun Young Park, Chong Woo Yoo, Myong Cheol Lim, Sang-Yoon Park and Byung Kiu Park
Cancers 2023, 15(21), 5290; https://doi.org/10.3390/cancers15215290 - 04 Nov 2023
Viewed by 983
Abstract
To investigate the outcomes of children, adolescents, and young adults (AYAs) with malignant ovarian germ cell tumors (MOGCTs), we analyzed the data of 61 patients aged ≤39 years diagnosed with MOGCT between 2006 and 2022. Among 59 patients who received chemotherapy after initial [...] Read more.
To investigate the outcomes of children, adolescents, and young adults (AYAs) with malignant ovarian germ cell tumors (MOGCTs), we analyzed the data of 61 patients aged ≤39 years diagnosed with MOGCT between 2006 and 2022. Among 59 patients who received chemotherapy after initial diagnosis, 57 received BEP (standard dose of bleomycin with 30 units per week, n = 13) or bEP (reduced dose of bleomycin with 15 units/m2 on day 1, n = 44). The 5-year overall survival (OS) and event-free survival (EFS) rates were 98.3% and 84.9%, respectively. Reduced bleomycin dose did not adversely affect survival. Normalization of tumor markers within 3 months after surgery was significantly associated with better EFS (p < 0.01). Of the 59 surviving patients, 8 experienced surgery-related menopause, while 49 demonstrated menstrual recovery. After completion of chemotherapy, there was no significant difference in pulmonary function regarding bleomycin dose, and no overt nephrotoxicity. Approximately 60% and 25% of survivors experienced peripheral neuropathy at the end of chemotherapy and after 1 year, respectively (p < 0.01). Children and AYAs with MOGCT have favorable survival rates with minimal long-term toxicity, which are not influenced by a reduced bleomycin dose. Rapid normalization of tumor markers is associated with improved outcomes. Full article
(This article belongs to the Section Cancer Therapy)
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18 pages, 10592 KiB  
Article
Identification of a Complex Karyotype Signature with Clinical Implications in AML and MDS-EB Using Gene Expression Profiling
by Cheonghwa Lee, Ha Nui Kim, Jung Ah Kwon, Jinha Hwang, Ji-Ye Park, Ok Sarah Shin, Soo-Young Yoon and Jung Yoon
Cancers 2023, 15(21), 5289; https://doi.org/10.3390/cancers15215289 - 04 Nov 2023
Cited by 1 | Viewed by 1141
Abstract
Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have [...] Read more.
Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have been rarely investigated. In this study, we developed and validated a CK-specific gene expression signature. Differential gene expression analysis between the CK and non-CK groups using data from 348 patients with AML and MDS-EB from four cohorts revealed enrichment of the downregulated genes localized on chromosome 5q or 7q, suggesting that haploinsufficiency due to the deletion of these chromosomes possibly underlies CK pathogenesis. We built a robust transcriptional model for CK prediction using LASSO regression for gene subset selection and validated it using the leave-one-out cross-validation method for fitting the logistic regression model. We established a 10-gene CK signature (CKS) predictive of CK with high predictive accuracy (accuracy 94.22%; AUC 0.977). CKS was significantly associated with shorter overall survival in three independent cohorts, and was comparable to that of previously established risk stratification models for AML. Furthermore, we explored of therapeutic targets among the genes comprising CKS and identified the dysregulated expression of superoxide dismutase 1 (SOD1) gene, which is potentially amenable to SOD1 inhibitors. Full article
(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)
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52 pages, 1086 KiB  
Review
Exploring Neoadjuvant Chemotherapy, Predictive Models, Radiomic, and Pathological Markers in Breast Cancer: A Comprehensive Review
by Basma Elsayed, Ahmed Alksas, Mohamed Shehata, Ali Mahmoud, Mona Zaky, Reham Alghandour, Khaled Abdelwahab, Mohamed Abdelkhalek, Mohammed Ghazal, Sohail Contractor, Hossam El-Din Moustafa and Ayman El-Baz
Cancers 2023, 15(21), 5288; https://doi.org/10.3390/cancers15215288 - 04 Nov 2023
Viewed by 1380
Abstract
Breast cancer retains its position as the most prevalent form of malignancy among females on a global scale. The careful selection of appropriate treatment for each patient holds paramount importance in effectively managing breast cancer. Neoadjuvant chemotherapy (NACT) plays a pivotal role in [...] Read more.
Breast cancer retains its position as the most prevalent form of malignancy among females on a global scale. The careful selection of appropriate treatment for each patient holds paramount importance in effectively managing breast cancer. Neoadjuvant chemotherapy (NACT) plays a pivotal role in the comprehensive treatment of this disease. Administering chemotherapy before surgery, NACT becomes a powerful tool in reducing tumor size, potentially enabling fewer invasive surgical procedures and even rendering initially inoperable tumors amenable to surgery. However, a significant challenge lies in the varying responses exhibited by different patients towards NACT. To address this challenge, researchers have focused on developing prediction models that can identify those who would benefit from NACT and those who would not. Such models have the potential to reduce treatment costs and contribute to a more efficient and accurate management of breast cancer. Therefore, this review has two objectives: first, to identify the most effective radiomic markers correlated with NACT response, and second, to explore whether integrating radiomic markers extracted from radiological images with pathological markers can enhance the predictive accuracy of NACT response. This review will delve into addressing these research questions and also shed light on the emerging research direction of leveraging artificial intelligence techniques for predicting NACT response, thereby shaping the future landscape of breast cancer treatment. Full article
(This article belongs to the Section Cancer Therapy)
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16 pages, 1402 KiB  
Article
Oncological Outcomes, Long-Term Toxicities, Quality of Life and Sexual Health after Pencil-Beam Scanning Proton Therapy in Patients with Low-Grade Glioma
by Jonas Willmann, Dominic Leiser and Damien Charles Weber
Cancers 2023, 15(21), 5287; https://doi.org/10.3390/cancers15215287 - 04 Nov 2023
Cited by 1 | Viewed by 845
Abstract
Purpose: To assess oncological outcomes, toxicities, quality of life (QoL) and sexual health (SH) of low-grade glioma (LGG) patients treated with pencil-beam scanning proton therapy (PBS-PT). Material and methods: We retrospectively analyzed 89 patients with LGG (Neurofibromatosis type 1; n = 4 (4.5%) [...] Read more.
Purpose: To assess oncological outcomes, toxicities, quality of life (QoL) and sexual health (SH) of low-grade glioma (LGG) patients treated with pencil-beam scanning proton therapy (PBS-PT). Material and methods: We retrospectively analyzed 89 patients with LGG (Neurofibromatosis type 1; n = 4 (4.5%) patients) treated with PBS-PT (median dose 54 Gy (RBE)) from 1999 to 2022 at our institution. QoL was prospectively assessed during PBS-PT and yearly during follow-up from 2015 to 2023, while a cross-sectional exploration of SH was conducted in 2023. Results: Most LGGs (n = 58; 65.2%) were CNS WHO grade 2 and approximately half (n = 43; 48.3%) were located in the vicinity of the visual apparatus/thalamus. After a median follow-up of 50.2 months, 24 (27%) patients presented with treatment failures and most of these (n = 17/24; 70.8%) were salvaged. The 4-year overall survival was 89.1%. Only 2 (2.2%) and 1 (1.1%) patients presented with CTCAE grade 4 and 3 late radiation-induced toxicity, respectively. No grade 5 late adverse event was observed. The global health as a domain of QoL remained stable and comparable to the reference values during PBS-PT and for six years thereafter. Sexual satisfaction was comparable to the normative population. Conclusions: LGG patients treated with PBS-PT achieved excellent long-term survival and tumor control, with exceptionally low rates of high-grade late toxicity, and favorable QoL and SH. Full article
(This article belongs to the Special Issue Low Grade Gliomas)
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14 pages, 1641 KiB  
Article
The Incidence of Rectal Neuroendocrine Tumors Is Increasing in Younger Adults in the US, 2001–2020
by Yazan Abboud, Navya Pendyala, Alexander Le, Anmol Mittal, Saqr Alsakarneh, Fouad Jaber and Kaveh Hajifathalian
Cancers 2023, 15(21), 5286; https://doi.org/10.3390/cancers15215286 - 04 Nov 2023
Viewed by 1087
Abstract
Prior non-comparative data showed increasing incidence of rectal neuroendocrine tumors (RNET) in the US. We aimed to evaluate age-specific RNET incidence rates and time-trends in demographic- and tumor-specific populations. The RNET age-adjusted incidence rates were calculated from the United States Cancer Statistics (USCS) [...] Read more.
Prior non-comparative data showed increasing incidence of rectal neuroendocrine tumors (RNET) in the US. We aimed to evaluate age-specific RNET incidence rates and time-trends in demographic- and tumor-specific populations. The RNET age-adjusted incidence rates were calculated from the United States Cancer Statistics (USCS) database between 2001 and 2020. The population was stratified by age into older (55 years) and younger adults (<55 years), as well as by sex and race. The tumors were categorized by their stage at diagnosis into early and late. The annual percentage change (APC) and average APC (AAPC) were estimated using joinpoint regression and Monte Carlo permutation analysis. Pairwise comparison assessed for parallelism and coincidence. There were 59,846 patients diagnosed with RNET between 2001 and 2020 (50.3% women). Overall, the RNET incidence rates during this period were increasing in younger but not older adults (AAPC = 3.12 vs. −1.10; AAPC difference = 4.22, p < 0.001), with non-identical non-parallel data (p-values < 0.001). While similar results were seen in men, a greater age-specific difference was noted in women (AAPC = 3.31 vs. −1.10; AAPC difference = 4.41, p = 0.003). The difference between younger and older adults was seen in non-Hispanic White (AAPC-difference = 4.89; p < 0.001) and non-Hispanic Black (AAPC-difference = 3.33; p = 0.03) patients, and, in most years, among Hispanic and Non-Hispanic Asian/Pacific Islander patients, and it was mostly driven by early-stage tumors (AAPC-difference = 3.93; p < 0.001). The nationwide data show a significantly increasing RNET incidence in younger adults, most notably in younger women and in early-stage tumors, seen in various races. Future studies should evaluate RNET risk factors and outcomes in demographic-specific populations. Full article
(This article belongs to the Special Issue Emerging Trends in Global Cancer Epidemiology)
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20 pages, 3307 KiB  
Article
Plasmacytoid Dendritic Cell, Slan+-Monocyte and Natural Killer Cell Counts Function as Blood Cell-Based Biomarkers for Predicting Responses to Immune Checkpoint Inhibitor Monotherapy in Non-Small Cell Lung Cancer Patients
by Francesca Pettinella, Chiara Lattanzi, Marta Donini, Elena Caveggion, Olivia Marini, Giulia Iannoto, Sara Costa, Elena Zenaro, Tiago Moderno Fortunato, Sara Gasperini, Matteo Giani, Lorenzo Belluomini, Marco Sposito, Jessica Insolda, Ilaria Mariangela Scaglione, Michele Milella, Annalisa Adamo, Ornella Poffe, Vincenzo Bronte, Stefano Dusi, Marco A. Cassatella, Stefano Ugel, Sara Pilotto and Patrizia Scapiniadd Show full author list remove Hide full author list
Cancers 2023, 15(21), 5285; https://doi.org/10.3390/cancers15215285 - 03 Nov 2023
Cited by 1 | Viewed by 871
Abstract
The advent of immune checkpoint inhibitors (ICIs), for instance, programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockers, has greatly improved the outcome of patients affected by non-small cell lung cancer (NSCLC). However, most NSCLC patients either do not respond to ICI monotherapy [...] Read more.
The advent of immune checkpoint inhibitors (ICIs), for instance, programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockers, has greatly improved the outcome of patients affected by non-small cell lung cancer (NSCLC). However, most NSCLC patients either do not respond to ICI monotherapy or develop resistance to it after an initial response. Therefore, the identification of biomarkers for predicting the response of patients to ICI monotherapy represents an urgent issue. Great efforts are currently dedicated toward identifying blood-based biomarkers to predict responses to ICI monotherapy. In this study, more commonly utilized blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR) and the lung immune prognostic index (LIPI) score, as well as the frequency/number and activation status of various types of circulating innate immune cell populations, were evaluated in NSCLC patients at baseline before therapy initiation. The data indicated that, among all the parameters tested, low plasmacytoid dendritic cell (pDC), slan+-monocyte and natural killer cell counts, as well as a high LIPI score and elevated PD-L1 expression levels on type 1 conventional DCs (cDC1s), were independently correlated with a negative response to ICI therapy in NSCLC patients. The results from this study suggest that the evaluation of innate immune cell numbers and phenotypes may provide novel and promising predictive biomarkers for ICI monotherapy in NSCLC patients. Full article
(This article belongs to the Special Issue Dendritic Cells in Cancer Immunology and Immunotherapy)
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14 pages, 2787 KiB  
Article
Exploring Cell Migration Mechanisms in Cancer: From Wound Healing Assays to Cellular Automata Models
by Giorgia Migliaccio, Rosalia Ferraro, Zhihui Wang, Vittorio Cristini, Prashant Dogra and Sergio Caserta
Cancers 2023, 15(21), 5284; https://doi.org/10.3390/cancers15215284 - 03 Nov 2023
Cited by 1 | Viewed by 1077
Abstract
Purpose: Cell migration is a critical driver of metastatic tumor spread, contributing significantly to cancer-related mortality. Yet, our understanding of the underlying mechanisms remains incomplete. Methods: In this study, a wound healing assay was employed to investigate cancer cell migratory behavior, with the [...] Read more.
Purpose: Cell migration is a critical driver of metastatic tumor spread, contributing significantly to cancer-related mortality. Yet, our understanding of the underlying mechanisms remains incomplete. Methods: In this study, a wound healing assay was employed to investigate cancer cell migratory behavior, with the aim of utilizing migration as a biomarker for invasiveness. To gain a comprehensive understanding of this complex system, we developed a computational model based on cellular automata (CA) and rigorously calibrated and validated it using in vitro data, including both tumoral and non-tumoral cell lines. Harnessing this CA-based framework, extensive numerical experiments were conducted and supported by local and global sensitivity analyses in order to identify the key biological parameters governing this process. Results: Our analyses led to the formulation of a power law equation derived from just a few input parameters that accurately describes the governing mechanism of wound healing. This groundbreaking research provides a powerful tool for the pharmaceutical industry. In fact, this approach proves invaluable for the discovery of novel compounds aimed at disrupting cell migration, assessing the efficacy of prospective drugs designed to impede cancer invasion, and evaluating the immune system’s responses. Full article
(This article belongs to the Special Issue Experimental and Modeling Efforts to Target Metabolism in Cancer)
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28 pages, 12195 KiB  
Article
Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L
by Xin Li, Xiaowei Wu, Shenyou Nie, Jidong Zhao, Yuan Yao, Fangrui Wu, Chandra Bhushan Mishra, Md Ashraf-Uz-Zaman, Bala Krishna Moku and Yongcheng Song
Cancers 2023, 15(21), 5283; https://doi.org/10.3390/cancers15215283 - 03 Nov 2023
Viewed by 868
Abstract
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several [...] Read more.
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC50 values as low as 1.6 μM. Structure–activity relationship studies of 77 benzothiophene and related indole and benzofuran compounds show that a 4-piperidin-1-ylphenyl or 4-pyrrolidin-1-ylphenyl substituent is essential for the activity. The inhibitors suppressed expression of MLL target genes HoxA9, Meis1 and Myc, and selectively inhibited proliferation of MLL-r and other acute myeloid leukemia cells with EC50 values as low as 4.7 μM. These inhibitors are useful chemical probes for biological studies of AF9/ENL, as well as pharmacological leads for further drug development against MLL-r and other leukemias. Full article
(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)
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20 pages, 5237 KiB  
Article
Synaptotagmin 1 Suppresses Colorectal Cancer Metastasis by Inhibiting ERK/MAPK Signaling-Mediated Tumor Cell Pseudopodial Formation and Migration
by Jianyun Shi, Wenjing Li, Zhenhua Jia, Ying Peng, Jiayi Hou, Ning Li, Ruijuan Meng, Wei Fu, Yanlin Feng, Lifei Wu, Lan Zhou, Deping Wang, Jing Shen, Jiasong Chang, Yanqiang Wang and Jimin Cao
Cancers 2023, 15(21), 5282; https://doi.org/10.3390/cancers15215282 - 03 Nov 2023
Cited by 1 | Viewed by 818
Abstract
Although synaptotagmin 1 (SYT1) has been identified participating in a variety of cancers, its role in colorectal cancer (CRC) remains an enigma. This study aimed to demonstrate the effect of SYT1 on CRC metastasis and the underlying mechanism. We first found that SYT1 [...] Read more.
Although synaptotagmin 1 (SYT1) has been identified participating in a variety of cancers, its role in colorectal cancer (CRC) remains an enigma. This study aimed to demonstrate the effect of SYT1 on CRC metastasis and the underlying mechanism. We first found that SYT1 expressions in CRC tissues were lower than in normal colorectal tissues from the CRC database and collected CRC patients. In addition to this, SYT1 expression was also lower in CRC cell lines than in the normal colorectal cell line. SYT1 expression was downregulated by TGF-β (an EMT mediator) in CRC cell lines. In vitro, SYT1 overexpression repressed pseudopodial formation and reduced cell migration and invasion of CRC cells. SYT1 overexpression also suppressed CRC metastasis in tumor-bearing nude mice in vivo. Moreover, SYT1 overexpression promoted the dephosphorylation of ERK1/2 and downregulated the expressions of Slug and Vimentin, two proteins tightly associated with EMT in tumor metastasis. In conclusion, SYT1 expression is downregulated in CRC. Overexpression of SYT1 suppresses CRC cell migration, invasion, and metastasis by inhibiting ERK/MAPK signaling-mediated CRC cell pseudopodial formation. The study suggests that SYT1 is a suppressor of CRC and may have the potential to be a therapeutic target for CRC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanisms of Gastrointestinal Tumors)
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20 pages, 4650 KiB  
Article
Enhancing the Accuracy of Lymph-Node-Metastasis Prediction in Gynecologic Malignancies Using Multimodal Federated Learning: Integrating CT, MRI, and PET/CT
by Zhijun Hu, Ling Ma, Yue Ding, Xuanxuan Zhao, Xiaohua Shi, Hongtao Lu and Kaijiang Liu
Cancers 2023, 15(21), 5281; https://doi.org/10.3390/cancers15215281 - 03 Nov 2023
Viewed by 746
Abstract
Gynecological malignancies, particularly lymph node metastasis, have presented a diagnostic challenge, even with traditional imaging techniques such as CT, MRI, and PET/CT. This study was conceived to explore and, subsequently, to bridge this diagnostic gap through a more holistic and innovative approach. By [...] Read more.
Gynecological malignancies, particularly lymph node metastasis, have presented a diagnostic challenge, even with traditional imaging techniques such as CT, MRI, and PET/CT. This study was conceived to explore and, subsequently, to bridge this diagnostic gap through a more holistic and innovative approach. By developing a comprehensive framework that integrates both non-image data and detailed MRI image analyses, this study harnessed the capabilities of a multimodal federated-learning model. Employing a composite neural network within a federated-learning environment, this study adeptly merged diverse data sources to enhance prediction accuracy. This was further complemented by a sophisticated deep convolutional neural network with an enhanced U-NET architecture for meticulous MRI image processing. Traditional imaging yielded sensitivities ranging from 32.63% to 57.69%. In contrast, the federated-learning model, without incorporating image data, achieved an impressive sensitivity of approximately 0.9231, which soared to 0.9412 with the integration of MRI data. Such advancements underscore the significant potential of this approach, suggesting that federated learning, especially when combined with MRI assessment data, can revolutionize lymph-node-metastasis detection in gynecological malignancies. This paves the way for more precise patient care, potentially transforming the current diagnostic paradigm and resulting in improved patient outcomes. Full article
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20 pages, 2299 KiB  
Article
Sorafenib Resistance Contributed by IL7 and MAL2 in Hepatocellular Carcinoma Can Be Overcome by Autophagy-Inducing Stapled Peptides
by Jeffrey C. To, Shan Gao, Xiao-Xiao Li, Yanxiang Zhao and Vincent W. Keng
Cancers 2023, 15(21), 5280; https://doi.org/10.3390/cancers15215280 - 03 Nov 2023
Viewed by 1096
Abstract
Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines [...] Read more.
Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines in order to identify potential drug resistant causative genes. Interleukin 7 (IL7) and mal, T cell differentiation protein 2 (MAL2) were identified as candidate genes that promote survival by activating JAK/STAT and PI3K/AKT signaling pathways. Sorafenib-resistant cells exhibited higher clonogenic survival and lower drug sensitivity due to IL7 and MAL2 upregulation. Higher anti-apoptotic effect, clonogenic survival and increased PI3K/AKT/STAT3 activities were observed in IL7 and MAL2 co-overexpressing cells compared with controls or cells overexpressing IL7 or MAL2 individually. Given the critical role of MAL2 in endocytosis, we propose that MAL2 might facilitate the endocytic trafficking of IL7 and its cognate receptors to the plasma membrane, which leads to upregulated JAK/STAT and PI3K/AKT signaling pathways and Sorafenib resistance. Additionally, our previous studies showed that an autophagy-inducing stapled peptide promoted the endolysosomal degradation of c-MET oncogene and overcame adaptive Sorafenib resistance in c-MET+ HCC cells. In this study, we demonstrate that these stapled peptides readily induced autophagy and inhibited the proliferation of both wild-type and Sorafenib-resistant HCC cells co-overexpressing both IL7 and MAL2. Furthermore, these peptides showed synergistic cytotoxicity with Sorafenib in drug-resistant HCC cells co-overexpressing both IL7 and MAL2. Our studies suggest that targeting autophagy may be a novel strategy to overcome IL7/MAL2-mediated Sorafenib resistance in HCC. Full article
(This article belongs to the Special Issue Autophagy and Therapy Resistance in Cancers)
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4 pages, 206 KiB  
Editorial
The New Face of Autophagy in Chronic Lymphocytic Leukemia
by Gelina S. Kopeina and Boris Zhivotovsky
Cancers 2023, 15(21), 5279; https://doi.org/10.3390/cancers15215279 - 03 Nov 2023
Viewed by 707
Abstract
Chronic lymphocytic leukemia (CLL) mainly afflicts adults and accounts for 25% of all new leukemia cases [...] Full article
(This article belongs to the Section Molecular Cancer Biology)
3 pages, 185 KiB  
Editorial
Special Issue: Childhood Brain Cancer Treatment
by Stefano Mastrangelo
Cancers 2023, 15(21), 5278; https://doi.org/10.3390/cancers15215278 - 03 Nov 2023
Viewed by 458
Abstract
Brain cancer is the second most common childhood malignancy and is the leading cause of death among all pediatric cancers [...] Full article
(This article belongs to the Special Issue Childhood Brain Cancer Treatment)
19 pages, 2950 KiB  
Review
RNA Editing in Cancer Progression
by Valentina Frezza, Lidia Chellini, Arianna Del Verme and Maria Paola Paronetto
Cancers 2023, 15(21), 5277; https://doi.org/10.3390/cancers15215277 - 03 Nov 2023
Cited by 1 | Viewed by 1278
Abstract
Coding and noncoding RNA molecules play their roles in ensuring cell function and tissue homeostasis in an ordered and systematic fashion. RNA chemical modifications can occur both at bases and ribose sugar, and, similarly to DNA and histone modifications, can be written, erased, [...] Read more.
Coding and noncoding RNA molecules play their roles in ensuring cell function and tissue homeostasis in an ordered and systematic fashion. RNA chemical modifications can occur both at bases and ribose sugar, and, similarly to DNA and histone modifications, can be written, erased, and recognized by the corresponding enzymes, thus modulating RNA activities and fine-tuning gene expression programs. RNA editing is one of the most prevalent and abundant forms of post-transcriptional RNA modification in normal physiological processes. By altering the sequences of mRNAs, it makes them different from the corresponding genomic template. Hence, edited mRNAs can produce protein isoforms that are functionally different from the corresponding genome-encoded variants. Abnormalities in regulatory enzymes and changes in RNA-modification patterns are closely associated with the occurrence and development of various human diseases, including cancer. To date, the roles played by RNA modifications in cancer are gathering increasing interest. In this review, we focus on the role of RNA editing in cancer transformation and provide a new perspective on its impact on tumorigenesis, by regulating cell proliferation, differentiation, invasion, migration, stemness, metabolism, and drug resistance. Full article
(This article belongs to the Section Molecular Cancer Biology)
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